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Antioxidant c-FLIP inhibits Fas ligand-induced NF-kB activation in a phosphatidylinositol 3-kinase/Akt-dependent manner.
Iyer-AKV; Azad-N; Talbot-S; Stehlik-C; Lu-B; Wang-L; Rojanasakul-Y
J Immunol 2011 Sep; 187(6):3256-3266
Fas ligand (FasL) belongs to the TNF family of death ligands, and its binding to the FasR leads to activation of several downstream signaling pathways and proteins, including NF-kB and PI3K/Akt. However, it is not known whether cross-talk exists between NF-?B and PI3K/Akt in the context of FasL signaling. We demonstrate using both human renal epithelial 293T cells and Jurkat T-lymphocyte cells that although FasL activates both Akt and NF-kB, Akt inhibits FasL-dependent NF-kB activity in a reactive oxygen species-dependent manner. Cellular FLICE-inhibitory protein (c-FLIP), an antioxidant and an important component of the death-inducing signaling complex, also represses NF-?B upstream of the regulatory IkB kinase-y protein subunit in the NF-kB signaling pathway, and positive cross-talk exists between Akt and c-FLIP in the context of inhibition of FasL-induced NF-kB activity. The presence of two death effector domains of c-FLIP and S-nitrosylation of its caspase-like domain were found to be important for mediating c-FLIP-dependent downregulation of NF-kB activity. Taken together, our study reveals a novel link between NF-kB and PI3K/Akt and establishes c-FLIP as an important regulator of FasL-mediated cell death.
Cell-biology; Cell-cultures; Cell-damage; Cell-function; Proteins; Humans; Antioxidants; Antioxidation; Immunology; Immune-reaction; Immunochemistry
Dr. Anand Krishnan V. Iyer, Department of Pharmaceutical Sciences, Hampton University, Hampton, VA 23668
Issue of Publication
The Journal of Immunology
IL; MA; VA; WV